Glucose is the primary fuel for the body and adequate supplies must be maintained to support the normal function of organs and tissues. Over the long term an excess of glucose intake results in weight gain and added risk for developing diabetes. Blood glucose is held within narrow limits to balance the supply and demand for energy and a major factor in this control is the transport of excess glucose into muscle and fat for storage. There are two classes of glucose transporters, GLUTs and SGLTs, but research on glucose transport in health and disease has focused on the GLUTs. SGLTs genes are expressed throughout the body indicating a larger role of these transporters in the transport of glucose into cells than anticipated. The goal is to elucidate the importance of SGLTs (sodium/glucose cotransporters) in the human physiology of glucose homeostasis and metabolism using Positron Emission Tomography (PET). The Introduction of the glucose probe 2-FDG and PET has revolutionized studies of glucose uptake and metabolism in organs and tissues in the human body. Clinically this has had an enormous impact in cancer detection, staging and therapy. However, 2-FDG is not a substrate for SGLTs and this has limited our understanding of glucose transport and metabolism in normal cells and tumors. The specific aims of this proposal are to: 1). Design PET probes specific for SGLTs;2). Synthesize [F-18]-labeled probes for SGLTs;and 3). Use PET imaging with these new glucose probes to examine the physiological role of SGLTs in animal and human subjects. The role of SGLT1 and SGLT2 in glucose uptakes will be tested by including in the study patients with mutations in the SGLTs genes, patients with Glucose- Galactose-Malabsorption and Familial Renal Glucosuria. In parallel, we will conduct studies using 2-FDG to determine the relative importance of GLUTs and SGLTs in glucose uptakes in organs of interest. Studies will also be carried out with both SGLT and GLUT probes on available rodents and SGLT and GLUT knockout mice to compliment the studies on patients. Clearly, identification of all the pathways for glucose uptake into cells is required for a full understanding of energy balance in health and disease. This project is designed to test the sorely neglected role of sodium glucose cotransporters in glucose homeostasis.Relevance Statement: This study of designed to determine the role of sodium/glucose cotransporters (SGLTs) in glucose homeostasis. SGLTs are expressed throughout the body but until now their role outside the intestinal kidneys has been neglected. The results of this study may provide new drug targets for diabetes and obesity and develop new PET tracers to detect and stage cancer. PUBLIC HEALTH RELEVANCE: This study is designed to determine the role of sodium/glucose cotransporters (SGLTs) in glucose homeostasis. SGLTs are expressed throughout the body but until now their role outside the intestine and kidneys has been neglected. The results of this study may provide new drug targets for diabetes and obesity and develop new PET tracers to detect and stage cancer.